1. Field of the Invention
The present invention relates to arylmethyl-carbonylaminothiazole derivatives and, more specifically relates to 2-(arylmethyl-carbonylamino)-1,3-thiazole derivatives, to a process for their preparation, to pharmaceutical compositions containing them, and to their use as therapeutic agents, particularly in the treatment of cancer and cell proliferative disorders.
2. Background of the Invention
Several cytotoxic drugs such as, e.g. fluorouracil (5-FU), doxorubicin and camptothecins, cause damage DNA or affect cellular metabolic pathways and thus cause, in many cases, an indirect block of the cell cycle. Therefore, by producing an irreversible damage to both normal and tumor cells, these agents result in a significant toxicity and side-effects.
In this respect, compounds capable of being highly specific antitumor agents by selectively leading to tumor cell arrest and apoptosis, with comparable efficacy but reduced toxicity than the currently available drugs, are desirable.
It is well known that progression through the cell cycle is governed by a series of checkpoint controls, otherwise referred to as restriction points, which are regulated by a family of enzymes known as the cyclin-dependent kinases (cdk).
In their turn, the cdks themselves are regulated at many levels such as, for instance, binding to cyclins.
The coordinated activation and inactivation of different cyclin/cdk complexes is necessary for normal progression through the cell cycle. Both the critical G1-S and G2-M transitions are controlled by the activation of different cyclin/cdk activities. In G1, both cyclin D/cdk4 and cyclin E/cdk2 are thought to mediate the onset of S-phase. Progression through S-phase requires the activity of cyclin A/cdk2 whereas the activation of cyclin A/cdc2 (cdkl) and cyclin B/cdc2 are required for the onset of metaphases. For a general reference to cyclins and cyclin-dependent kinases see, for example, Kevin R. Webster et al. in Exp. Opin. Invest. Drugs, 1998, Vol. 7(6), 865-887.
Checkpoint controls are defective in tumor cells due, in part, to disregulation of cdk activity. For example, altered expression of cyclin E and cdk""s has been observed in tumor cells, and deletion of the cdk inhibitor p27 KIP gene in mice has been shown to result in a higher incidence of cancer.
Increasing evidence supports the idea that the cdks are rate-limiting enzymes in cell cycle progression and, as such, represent molecular targets for therapeutic intervention. In particular, the direct inhibition of cdk/cyclin kinase activity should be helpful in restricting the unregulated proliferation of a tumor cell.
It is an object of the invention to provide compounds which are useful in treating cell proliferative disorders associated with an altered cell dependent kinase activity. It is another object to provide compounds which have cdk/cyclin kinase inhibitory activity.
It is another object of the invention to provide compounds which are useful in therapy as antitumor agents but lack, in terms of both toxicity and side effects, the drawbacks associated with currently available antitumor drugs discussed above.
The present inventors have now discovered that 2-amino-1,3-thiazole derivatives are endowed with cdk/cyclin kinase inhibitory activity and are thus useful in therapy as antitumor agents and lack, in terms of both toxicity and side effects, the aforementioned drawbacks associated with currently available antitumor drugs.
More specifically, the compounds of this invention are useful in the treatment of a variety of cancers including, but not limited to: carcinoma such as bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin""s lymphoma, non-Hodgkin""s lymphoma, hairy cell lymphoma and Burkett""s lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi""s sarcoma.
Due to the key role of cdks in the regulation of cellular proliferation, the 2-amino-1,3-thiazole derivatives are also useful in the treatment of a variety of cell proliferative disorders such as, for instance, benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
The compounds of the invention can be useful in the treatment of Alzheimer""s disease, as suggested by the fact that cdk5 is involved in the phosphorylation of tau protein (J. Biochem., 17, 741-749, 1995).
The compounds of this invention, as modulators of apoptosis, could be useful in the treatment of cancer, viral infections, prevention of AIDS development in HIV-infected individuals, autoimmune diseases and neurodegenerative disorder.
The compounds of this invention may also be useful in inhibiting tumor angiogenesis and metastasis.
The compounds of this invention may also act as inhibitors of other protein kinases, e.g. protein kinase C, her2, rafl, MEKI, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, P13 kinase, weel kinase, Src, Abl and thus be effective in the treatment of diseases associated with other protein kinases.
Accordingly, the present invention provides a method for the treatment of cell proliferative disorders associated with an altered cell dependent kinase activity, by administering to a mammal in need thereof an effective amount of a 2-amino-1,3-thiazole represented by formula (I) or (II): 
where
L is a phenyl group or a 5 or 6 membered aromatic heterocycle with one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;
R is (i) a halogen atom, a nitro group, or it is selected from the group consisting of pyrrolidino, morpholino, piperazino, N-alkyl piperazino, N-aryl-piperazino, N-arylalkyl-piperazino, piperidino and azabicyclo[3.2.2]nonane; or
(ii) an amino group optionally further substituted with one or more groups, which may be the same or different, selected from the group consisting of alkyl, aryl, arylalkyl, alkylsulphonyl, arylsulphonyl, arylalkylsulphonyl, alkylcarbonyl, arylcarbonyl, and arylalkylcarbonyl, wherein the alkyl moieties therein are optionally further substituted with one or more hydroxy or amino groups; or
(iii) a C3-C6 cycloalkyl optionally substituted with a straight or branched C1-C6 alkyl group; or
(iv) a straight or branched C1-C6 alkyl group or an arylalkyl group which is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, carboxy, hydroxy, nitro, alkylthio, alkoxy, straight or branched C1-C6 alkyl, arylthio, aryloxy, amino, alkylamino, dialkylamino, arylamino, arylalkylamino, hydroxyaminocarbonyl, alkoxyaminocarbonyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, alkyl-C3-C6 cycloalkyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkylsulphonyl, arylsulphonyl, arylalkylsulphonyl, aminosulphonyl, alkylaminosulphonyl, dialkylaminosulphonyl, alkylcarbonylamino, arylalkylcarbonylamino, arylaminosulphonyl, arylalkylaminosulphonyl, arylcarbonylamino, alkylsulphonylamino, arylsulphonylamino, arylalkylsulphonylamino, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, arylalkylaminocarbonyl, pyrrolidino, morpholino, piperazino, N-alkylpiperazino, N-aryl-piperazino, N-arylalkyl-piperazino, piperidino, and azabicyclo[3.2.2]nonane; or
(v) an aryl group which is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, carboxy, hydroxy, nitro, alkylthio, alkoxy, straight or branched C1-C6 alkyl, arylthio, aryloxy, amino, alkylamino, dialkylamino, arylamino, arylalkylamino, hydroxyaminocarbonyl, alkoxyaminocarbonyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, alkyl-C3-C6 cycloalkyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkylsulphonyl, arylsulphonyl, arylalkylsulphonyl, aminosulphonyl, alkylaminosulphonyl, dialkylaminosulphonyl, alkylcarbonylamino, arylalkylcarbonylamino, arylaminosulphonyl, arylalkylaminosulphonyl, arylcarbonylamino, alkylsulphonylamino, arylsulphonylamino, arylalkylsulphonylamino, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, arylalkylaminocarbonyl, pyrrolidino, morpholino, piperazino, N-alkylpiperazino, N-aryl-piperazino, N-arylalkyl-piperazino, piperidino, and azabicyclo[3.2.2]nonane;
R1 is a hydrogen atom or a straight or branched C1-C4 alkyl group optionally substituted with one or more hydroxy, alkoxy, amino, alkylamino, or dialkylamino groups;
R2 and R3, which may be the same or different, are a hydrogen atom, a cycloalkyl group, a straight or branched C1-C6 alkyl group or an aryl group, which are each optionally substituted as described above for R; or
R2 and R3, together with the nitrogen atom to which they are bonded, form a 4-morpholinyl, 1-piperazinyl, N-alkyl-piperazinyl, N-aryl-piperazinyl, N-arylalkyl-piperazinyl, piperidinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, imidazolyl or 3-azabicyclo[3.2.2]nonyl ring;
R4 is carboxy, a perfluorinated alkyl group, a C2-C4 alkynyl group, 2-oxo-pyrrolidinyl, piperidinyl or a straight or branched C1-C6 alkyl group or an aryl group, which is optionally substituted as described above for R;
or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the invention, the cell proliferative disorder is selected from the group consisting of cancer, Alzheimer""s disease, viral infections, auto-immune diseases or neurodegenerative disorders.
Specific types of cancer that may be treated include carcinoma, squamous cell carcinoma, hematopoietic tumors of myeloid or lymphoid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi""s sarcoma.
In another preferred embodiment of the method described above, the cell proliferative disorder is selected from the group consisting of benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis, and post-surgical stenosis and restenosis.
In addition, the inventive method may provide for tumor angiogenesis and metastasis inhibition. The inventive method may also provide for cell cycle inhibition or cdk/cyclin dependent inhibition.
The present invention also provides a 2-amino-1,3-thiazole represented by formula (I) or (II): 
where
L is a phenyl group or a 5 or 6 membered aromatic heterocycle with one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;
R is (i) a halogen atom, a nitro group, or it is selected from the group consisting of pyrrolidino, morpholino, piperazino, N-alkyl, piperazino, N-aryl-piperazino, N-arylalkyl-piperazino, piperidino. and azabicyclo[3.2.2]nonane, or
(ii) an amino group optionally further substituted with one or more groups, which are the same or different, selected from the group consisting of alkyl, aryl, arylalkyl, alkylsulphonyl, arylsulphonyl, arylalkylsulphonyl, alkylcarbonyl, arylcarbonyl, and arylalkylcarbonyl, wherein the alkyl moiety therein is optionally further substituted with one or more hydroxy or amino groups; or
(iii) a C3-C6 cycloalkyl optionally substituted with a straight or branched C1-C6 alkyl group; or
(iv) a straight or branched C1-C6 alkyl group or an arylalkyl group, which is optionally substituted with one or more halogen, cyano, carboxy, hydroxy, nitro, alkylthio, alkoxy, straight or branched C1-C6 alkyl, arylthio, aryloxy, amino, alkylamino, dialkylamino, arylamino, arylalkylamino, hydroxyaminocarbonyl, alkoxyaminocarbonyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, alkyl-C3-C6 cycloalkyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkylsulphonyl, arylsulphonyl, arylalkylsulphonyl, aminosulphonyl, alkylaminosulphonyl, arylaminosulphonyl, dialkylaminosulphonyl, alkyl carbonylamino, arylalkylaminosulphonyl, arylcarbonylamino, arylalkylcarbonylamino, alkylsulphonylamino, arylsulphonylamino, arylalkylsulphonylamino, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, arylalkylaminocarbonyl, pyrrolidino, morpholino, piperazino, N-alkylpiperazino, N-aryl-piperazino, N-arylalkyl-piperazino, piperidino or azabicyclo[3.2.2]nonane substituents; or
(v) an aryl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, carboxy, hydroxy, nitro, alkylthio, alkoxy, straight or branched C1-C6 alkyl, arylthio, aryloxy, amino, alkylamino, dialkylamino, arylamino, arylalkylamino, hydroxyaminocarbonyl, alkoxyaminocarbonyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, alkyl-C3-C6 cycloalkyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkylsulphonyl, arylsulphonyl, arylalkylsulphonyl, aminosulphonyl, alkyl aminosulphonyl, arylaminosulphonyl, dialkylaminosulphonyl, alkylcarbonylamino, arylalkylaminosulphonyl, arylcarbonylamino, arylalkylcarbonylamino, alkylsulphonylamino, arylsulphonylamino, arylalkylsulphonylamino, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, arylalkylaminocarbonyl, pyrrolidino, morpholino, piperazino, N-alkylpiperazino, N-aryl-piperazino, N-arylalkyl-piperazino, piperidino and azabicyclo[3.2.2]nonane;
R1 is a hydrogen atom or a straight or branched C1-C4 alkyl group optionally substituted with one or more hydroxy, alkoxy, amino, alkylamino, or dialkylamino group;
R2 and R3, which may be the same or different, are a hydrogen atom, a cycloalkyl group, a straight or branched C1-C6 alkyl group or an aryl group, which are each optionally substituted as described above for R; or
R2 and R3, together with the nitrogen atom to which they are bonded, form a 4-morpholinyl, 1-piperazinyl, N-alkyl-piperazinyl, N-aryl-piperazinyl, N-arylalkyl-piperazinyl, piperidinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, imidazolyl or 3-azabicyclo[3.2.2]nonyl ring;
R4 is carboxy, a perfluorinated alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, 2-oxopyrrolidinyl, piperidinyl or a straight or branched C1-C6 alkyl group or an aryl group, which is optionally substituted as described above for R;
or a pharmaceutically acceptable salt thereof.
The present invention also provides a process for preparing the 2-amino-1,3-thiazole derivative described above, or a pharmaceutically acceptable salt thereof, by:
reacting a compound represented by formula (III): 
with a compound represented by formula (IV): 
where
R, L, R1, R2 and R3 are as defined above, and
Z is hydroxy or a suitable leaving group, to produce a 2-amino-1,3-thiazole derivative represented by formula (1), where R, L, R1, R2 and R3 are as defined above.
The present invention also provides a process for preparing the 2-amino-1,3-thiazole derivative described above, or a pharmaceutically acceptable salt thereof, by:
reacting a compound represented by formula (I): 
with a compound represented by formula (V):
R4xe2x80x94COXxe2x80x83xe2x80x83(V)
where
R, R1, L and R4 are as defined above, and
X is hydroxy or a suitable leaving group, such as chlorine or bromine,
to produce a 2-amino-1,3-thiazole derivative represented by formula (II), where R, L, R1 and R4 are as defined above.
The present invention also provides a process for preparing the 2-amino-1,3-thiazole derivative described above, or a pharmaceutically acceptable salt thereof, by:
reacting a 2-amino-1,3-thiazole derivative represented by formula (I), where both or at least one of R2 and R3 is a hydrogen atom, with a compound represented by formula (VI):
Rxe2x80x2Yxe2x80x83xe2x80x83(VI)
where
Rxe2x80x2 has the meanings of R2 or R3 but is other than hydrogen, and
Y is a suitable leaving group,
to produce a 2-amino-1,3-thiazole derivative of formula (I) where both or at least one of R2 and R3 is other than hydrogen; and, optionally, converting a 2-amino-1,3-thiazole derivative represented by formula (I) or (II) into another 2-amino-1,3-thiazole derivative represented by formula (I) or (II), and/or into a salt thereof.
The present invention also provides a pharmaceutical composition, containing the 2-amino-1,3-thiazole derivative described above and at least one pharmaceutically acceptable carrier and/or diluent.
A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following detailed description.